The papilloma viruses are non-encased viruses, the genome of which is formed by double strand DNA of about 8 kb. They are very widespread in nature and cause epithelial lesions in human as well as in many animals including rabbits, horses, dogs, and bovine species. More than a hundred human papilloma viruses (HPV) have been described. They are classified depending on their infection sites. About 30 HVP have been isolated from anogenital mucosas (cervix uteri, vagina, valva, penis, anus, rectum). The other HPVs are associated with skin lesions. The HPVs with cutaneous tropism include i.a., HPV1, HPV2, HPV3, HPV4, HPV5, HPV7, HPV8, HPV9, HPV10, HPV12, HPV14, HPV15, HPV17, HPV19, HPV20, HPV21, HPV22, HPV23, HPV24, HPV25, HPV26, HPV27, HPV28, HPV29, HPV38, HPV41, HPV47, HPV49. They are associated with lesions such as warts (verruca vulgaris, verruca plantaris, myrmecia wart, surface wart, verruca plana . . . ) and diseases such as epidermo-dysplasia verruciformis.
The mucogenital type HPVs are involved in laryngeal and anogenital diseases including certain cancers. They are often classified as high risk HPVs and low risk HPVs, with reference to the type of lesions with which they are associated. The low risk HPVs include, i.a., HPV6, HPV11, HPV13, HPV32, HPV34, HPV40, HPV42, HPV43, HPV44, HPV53, HPV54, HPV55, HPV57, HPV58, HPV74, HPV91.
The low risk HPVs are associated with benign lesions such as condylomas (genital warts such as acuminated condylomas and plane condylomas), laryngeal, conjunctive or buccal papillomas or other epithelial lesions such as intra-epithelial neoplasias of low grade or recurrent respiratory papillomatoses, and more rarely bowenoid papuloses or high grade intra-epithelial neoplasias or carcinomas. High risk HPVs include i.a., HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV59, HPV61, HPV62, HPV66, HPV67, HPV68, HPV72. They are involved in low grade intra-epithelial lesions which may develop into higher grade lesions right up to cancers, in particular cervix uteri cancer and other anogenital cancers.
Genital infections by HPVs are the most frequent sexually transmitted infections in the world, including in the developed countries with more than 20 million people infected in the United States. Prevalence of HPV infections varies from 3-42% depending on the countries and affects 10-20% of the sexually active population in industrialized countries. In part of this population, the infection persists and may lead to cancers in the case of high risk HPVs.
The prevalence of genital warts (condylomas) is estimated to be 1-2% in the sexually active population of industrialized countries, i.e. about 3,500,000 new cases every year in these countries and 28,000,000 worldwide. Genital warts may be found on parts of the body comprising the anus, vulva, vagina, cervix uteri and penis or peripheral bodies thereto.
Treatments of genital warts are based on several strategies, from physical destruction (cryotherapy, CO2 laser, electro-surgery, surgical excision), application of cytotoxic agents (TCA, podophyllin, podofilox) right up to the application of immuno-modulator agents (interferon, imiquimod). However, none of these methods completely eliminates all the viral particles, and significant rates of recurrence, accompanied by severe secondary effects are observed with present therapeutic strategies. This reinforces a need for new strategies for controlling or eliminating infections by papilloma viruses.
Unlike what exists in the treatment of other viral diseases, such as those caused by HIV, herpes viruses or influenza viruses, to this day there is no antiviral treatment which specifically targets viral pathogens which the papilloma viruses are.
The papilloma viruses infect multistratified epitheliums and their viral cycle is closely related to organogenesis of theses organs and to differentiation of keratinocytes. After infection, the viral genome is present and replicated in a small number in basal cells of the epithelium. As the cells gradually differentiate, the expression of the viral genes and the number of copies of the viral genome increase until expression of the genes of the viral capsid and formation of infectious virions in totally differentiated keratinocytes.
The genome of HPVs potentially codes for about ten proteins. The earliest expressed proteins, E1 and E2, are involved in the replication of the viral genome and the regulation of the expression of the viral genes. The other early proteins of these viruses (E4, E5, E6, E7) have functions in relationship with cell proliferation or roles which are not yet completely explained. The existence of E3 and E8 proteins is still uncertain. Late proteins L1 and L2 are those which form the viral capsid.
The only 2 viral proteins required and sufficient for replicating HPVs are E1 and E2. They are capable of forming an E1/E2 complex and of binding on the replication origin (Ori) of the HPVs, a sequence contained in the viral genome and bearing close sites recognized by E1 and by E2. E2 is capable of binding with very high affinity to the E2 sites whereas E1, alone, does not have very high affinity for E1 sites. The interaction between E1 and E2 increases binding of E1 on Ori by cooperative binding to DNA. Once it is bound to DNA, E1 no longer interacts with E2 but forms a hexamer. The helicase and ATPase activities of E1 allow unfolding of the viral DNA which is then replicated by the cell replication mechanism.
The inventors have sought to develop small molecules which inhibit replication of HPVs, preferably with a low risk, by notably interfering with the formation of the complex between the E1 and E2 proteins.
A solution was found by elaborating novel derivatives.